PHAGE THERAPY FOR ANTIMICROBIAL RESISTANCE: BENEFITS, RISKS, AND ADVANCES

Medically Reviewed by Dr. Sony Sherpa (MBBS), 1 July, 2024

Antimicrobial resistance (AMR) is an escalating worldwide health concern, with bacteria becoming increasingly antibiotic-resistant and claiming an estimated average of 4.95 million lives in 2019^[1].

Imagine a patient suffering from a severe lung infection caused by antibiotic-resistant bacteria like Acinetobacter baumannii. Despite multiple antibiotic courses, the infection persists, leading to complications such as difficulty breathing and a weakened immune system. If left untreated, such an infection can be potentially life-threatening.

AMR not only breeds chronic superbug infections but also compounds the symptoms with antibiotic medication side effects, often clogging up the body's elimination routes and lowering its ability to fend off the infection. The side effects can also lead to digestive problems, brain fog, chronic fatigue, depression, and more.

Scenarios like this one affect millions of individuals yearly, spurring the search for alternative treatments^[2]. One promising option is phage therapy, which uses predatory viruses, known as bacteriophages, that target resistant bugs without destroying the patient's internal ecology.

This article will examine what phage therapy is, how it compares to antibiotics, its advantages and limitations, current applications, safety and regulations, and the latest research and advancements in this field.

What is Phage Therapy?

Phage therapy, also known as bacteriophage therapy, is a treatment that uses viruses called bacteriophages to target and kill specific bacteria. Bacteriophages refer to predatory viruses that infect and replicate inside bacterial cells, thereby killing them. They are highly specific, only targeting certain strains of bacteria and leaving other bacteria and human cells unharmed.

Bacteria resistant to multiple antibiotics, known as superbugs, are a significant threat to healthcare systems around the globe. Phage therapy offers a potential solution to this problem, as phages can target and kill these bacteria.

Phages have been used successfully to treat infections caused by superbugs such as MRSA (methicillin-resistant Staphylococcus aureus) and CRE (Carbapenem-Resistant Enterobacteriaceae).

Other common pathogenic targets include:

• Escherichia coli
• Klebsiella pneumoniae
• Pseudomonas aeruginosa
• Acinetobacter baumannii

Phage Types and Therapy Development

Different types of phages can be used in phage therapy, including:

• Lytic phages: These phages kill bacteria by causing them to burst. This is the preferred type of phage used during treatment.
• Lysogenic phages: These phages integrate their genetic material into the bacterial DNA, potentially transferring genes between bacteria. After some time, this can cause the pathogen to die off, yet it may also increase bacterial resistance.

Phage therapy is still in its early stages of development. While some preparations already exist that target specific bacteria and bacterial collectives, scientists are still learning about bacteriophages capable of targeting patient-specific infections.

Bacteriophages thrive in all ecologies on the planet that house bacteria, including soil, water, and decomposing plant matter exposed to different environmental conditions. Hundreds and thousands of viruses are being reviewed and screened for their potential against chronic infections and illness. From these, "phage cocktails," assortments of different phages that target specific microbes, are under development.

Phage Delivery

The best administration route for phage preparations is one in which the particle delivery places them in direct contact with the target pathogenic bacteria. The most common routes of administration are capsules, which protect phages from stomach acid and allow them to reach the site of a gastrointestinal infection.^[3]

Other routes currently under scientific investigation include:

• Phage powder, lotion, or gauze for treating skin infections
• Aerosolized phage preparations for respiratory infections
• Phage infusions for bloodstream infections

Phage Therapy vs. Antibiotics

While both treatments target pathogenic organisms, the main difference between phage therapy and antibiotics is their mode of action.

Antibiotics destroy or impede the growth of a comprehensive spectrum of bacteria. Unfortunately, this range includes beneficial bacteria in the body. The gut microbiome is the first line of defense against pathogens. If antibiotics weaken the gut microbiome, AMR bacteria can over-populate it, leading to chronic infections and leaving the body more vulnerable to other threats.

On the other hand, viral phage therapy only infects the specific bacteria causing the infection, leaving the rest of the microbiome intact. This allows for the infection to pass without compromising long-term innate immunity.

Another key difference is the development of resistance. It is easier for bacteria to become resistant to antibiotics than they become resistant to predatory phages. This is because phages can evolve and adapt to changes in bacteria, making them less likely to develop resistance.

Mechanisms that pathogens can become resistant to antibiotics include^[4]:

• Efflux pumps that remove antibiotics from target bacteria and diminish their effectiveness
• Enzymes that alter antibiotic functionality
• Altered target sites and bacterial metabolism that impede antibiotic actions
• Overexpression of antimicrobial binding sites that decrease their effectiveness
• Biofilm formation that enhances resistance, lowers permeability, and limits drug contact
• Resistant gene transfer that strengthens bacterial pools
• The ability to penetrate and survive inside cells while avoiding antibiotic exposure

In some cases, bacteria have become resistant to phages, yet this adaptation often causes them to become less resistant to antibiotics and helps to enhance therapy.

Advantages of Phage Therapy

Phage therapy maintains several benefits over standard antibiotics. These include:

• Personalized medicine with high specificity: Like any virus, phages consist of viral mRNA. They can be genetically programmed to target specific strains of pathogenic bacteria, leaving beneficial bacteria and human cells unharmed. This customization makes phages the perfect personalized treatment option for resistant infections.
• High efficacy: Phages are highly effective at killing bacteria, even those resistant to multiple antibiotic types.
• Low toxicity: Phages are naturally occurring and are generally safe for use. They can reduce the use of antibiotics, their side effects, and disruption of the microbiome, contributing towards lower inflammation levels and a healthier state of innate immunity post-infection.
• Potential for use in biofilms: Biofilms are communities of bacteria highly resistant to antibiotics. Phages can penetrate biofilms and kill the bacteria within.
• Phage-Antibiotic Combinations: Using phages alongside antibiotics may allow for a lower dose of antibiotics, easing the burden of side effects and slowing the development of resistance.

Current Applications of Phage Therapy

Phage therapy approval is widespread for research purposes, with many countries regulating its investigation around the globe.

In several other countries, it is an experimental therapy that one may use if antibiotics and other treatments fail to work. These include Poland, the United Kingdom, France, Belgium, Australia, India, China, and the United States^[5]. These countries have pioneered the application of phage therapy and paved the way for its recognition as a viable treatment option.

Phage therapy is applicable in treating a wide range of infections and is especially useful in chronic infections:

Skin Infections and Wound Healing

Phage therapy presents a promising alternative to overcoming stubborn necrotic skin infections while facilitating wound healing, especially when traditional antibiotics fall short. Studies demonstrate the effectiveness of phages in targeting various wound-infecting bacteria, including antibiotic-resistant strains like methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, and Acinetobacter baumannii. This targeted approach allows phages to eliminate harmful bacteria without disrupting the natural skin microbiome, unlike broad-spectrum antibiotics.^[6]

Additionally, phage therapy has shown potential in stimulating wound healing processes, further aiding in the recovery of chronic and difficult-to-treat wounds, such as:

• Diabetic foot ulcers
• Venous leg ulcers
• Pressure ulcers
• Burn wounds
• Surgical site infections
• Traumatic wounds

Gastrointestinal Infections and Foodborne Illnesses

Phage therapy shows remarkable potential in addressing a range of foodborne illnesses and gastrointestinal infections. For food safety, phages can target bacteria like E. coli, Salmonella, Listeria monocytogenes, and Campylobacter, helping to prevent contamination and outbreaks^[7].

In gastrointestinal health, phage therapy may combat severe infections like those caused by Clostridioides Difficile (C. diff), often linked to antibiotic overuse. It could also aid in treating Shigellosis, reducing the severity of diarrhea caused by the Shigella bacteria, and lowering the appearance of helicobacter pylori and related stomach ulcers.^[8]

Additionally, research suggests that phage therapy might help manage inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, by targeting harmful bacteria that intensify symptoms, potentially regulating the gut microbiome and related inflammation.

Respiratory Infections

Phage therapy offers a unique approach to combat respiratory infections by directly targeting the harmful bacteria within the lungs. Inhaled phage preparations can reach infected areas, potentially killing specific bacterial infections, such as Klebsiella pneumonia and streptococcus pneumonia. This targeted action helps preserve beneficial bacteria in the respiratory system, promoting a healthy microbiome that aids in overall respiratory health.^[9]

For patients with cystic fibrosis, who frequently struggle with chronic lung infections, phage therapy could provide an alternative or complementary treatment to antibiotics, potentially improving outcomes and reducing the burden of antibiotic resistance.

Urinary Tract Infections

Phage therapy can target and treat UTIs by delivering phage preparations designed for bladder delivery. This approach can combat bacteria like Escherichia coli while preserving the beneficial bacteria in the urinary tract. With rising antibiotic resistance in UTI treatment, phage therapy could be a promising alternative or complement to antibiotics, improving patient outcomes.^[10]

Sensitive Populations

Across studies, phage therapy is generally safe, even for immunocompromised individuals and children.

For children susceptible to chronic infections, phage therapy can help them establish a thriving microbiome and avoid developmental complications related to chronic illness.^[11]

In immune-compromised patients, case studies reveal that phage therapy can clear up multidrug-resistant infections without causing side effects.^[12]

Is Phage Therapy Safe?

Phage therapy is generally considered safe, with minimal side effects reported. However, as with any medical treatment, there are risks involved. These include the potential for phages to cause harm to beneficial bacteria in the body and the potential for phages to transfer genes between bacteria.

More research is needed to understand the safety of phage therapy fully.

Challenges and Limitations

While phage therapy has many potential benefits, some challenges and limitations need addressing.

The safety and regulation of phage therapy is an important consideration. While phages are generally considered safe, there are still concerns about their potential long-term effects and interactions with the human immune system. In the United States and many other countries, the FDA and other authorities register phage therapy as an investigational new drug (IND) for clinical trials or under compassionate use exemptions.

Other challenges that need addressing include:

• Limited knowledge of phages: There is still much to learn about phages, including their interactions with the human immune system and their potential long-term effects.
• Limited availability: Phages are highly specific and must be matched to the specific bacterial strain causing the infection. An extensive collection of phages is necessary for effective treatment.

Latest Research and Advancements

Research into phage therapy is ongoing, and advancements are constant. Most recent developments are working towards building global safety standards for phage therapy and ascertaining their full scope of action. Several clinical trials are underway to test specific phage cocktails against many pathogens, including those highlighted above.

Here are some of the latest advances in phage therapy:

Genetic modification of phages for enhanced outcomes. Scientists are modifying phage genomes to tackle the problem of bacterial resistance to phages^[13] and to improve their scope of action. Strategies involve:

• Pinpointing the genes bacteria use to resist phages and then editing phage genomes to circumvent these defenses.
• Combining multiple phages that each target different bacterial receptors makes it more difficult for target bacteria to acquire complete resistance.
• Modification to withstand harsh environments and prolong their storage and administration viability.
• Engineering phages to bind to specific receptors on cancer cells or pathogens improves precision and lowers potential side effects.

Extraction of phage enzymes and proteins. Endolysins are enzymes phages produce during the infection process that break down bacterial cell walls. They have potential as standalone therapeutics, capable of swiftly destroying bacterial cells and offering a fast-acting alternative to some antibiotics^[14].

Enhancing Phage Delivery and Stability. Researchers are focusing on improving phage delivery to infection sites and increasing their longevity in the body.

• Encapsulating phages in nanoparticles or liposomes can protect them from degradation and help them reach specific tissues more effectively.^[15]
• Altering the surface chemistry of phages can increase their stability and circulation time within the body.

Applications Beyond Resistant Infections

Other phage therapy applications include tumor treatment, vaccine enhancement, and food safety.

Cancer: Phage therapy is revolutionizing oncology treatments, specifically with its applications in gene therapy, vaccines, and immunotherapy^[16]:

• Phages can deliver therapeutic genes to cancer cells that extinguish them, make them more susceptible to treatment, or enhance the immune system’s ability to respond to the tumor.
• Modified phages can help overcome some limitations of traditional gene therapy vectors by penetrating tumors more effectively and potentially evading immune system clearance.
• Phages can help improve immunotherapy by altering the tumor microbiome or directly targeting immune-suppressing cells. This enhances the effectiveness of immunotherapy.
• Combining phage therapy with checkpoint inhibitors could enhance anti-tumor responses by boosting immune response and improving treatment outcomes.
• Phage therapy's ability to target precise tumor types and individual patients highlights its potential in personalized cancer medicine.

Vaccines: Scientists are exploring using phages in vaccines as phages can destroy target bacteria and improve the immune system's response to tumors and pathogens. Mechanisms include:

• Altered phages can display tumor antigens and other foreign proteins on their surface. They act as a vaccine platform that triggers a more robust immune response against pathogens or cancer cells expressing specific antigens.
• They can act as adjuvants, enhancing the overall immune response and potentially stimulating anti-tumor immunity, making the vaccine more effective.

Agriculture & Food Safety: Beyond human medicine, Phage therapy holds vast potential for combating bacterial diseases and contamination in agriculture and food production. Therapy may lower infections in livestock, plants, and food products, ensuring better quality and food safety.

Conclusion

Phage therapy is a promising alternative to antibiotics for treating bacterial infections. It offers several advantages, including high specificity, personalized medicine, and low toxicity. While challenges and limitations still need to be addressed, ongoing research and advancements are making phage therapy a more viable option for treating antimicrobial-resistant infections. With further research and development, phage therapy has the potential to revolutionize the way we treat bacterial infections.

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